出版社：American Society for Biochemistry and Molecular Biology
摘要：Pluronic L81 (PL81) inhibits fat absorption, and other Pluroniccopolymers help overcome drug resistance in cancer cells. Tounderstand how PL81 acts, we synthesized a radiolabeled analog,[14C]PL81, and showed that it was structurally similar to PL81based on 1H NMR as well as mass spectrometric analysis. [14C]PL81inhibited the secretion of chylomicrons (CMs), lipoproteinsessential for fat absorption, by differentiated Caco-2 cellssimilar to PL81. Moreover, PL81 competed with the cellular uptakeof [14C]PL81. Thus, [14C]PL81 and PL81 behave similarly in thesephysiologic assays. Uptake of [14C]PL81 by Caco-2 cells wasconcentration-, time-, and temperature-dependent and occurredmainly from the apical side. Intracellularly, it was assimilatedin the cytosol. Cells excreted PL81 toward the apical side viaa pathway partially sensitive to verapamil. Small amounts weresecreted toward the basolateral side unassociated with CM, andthis secretion was unaffected by the inhibition of CM assembly.Nonetheless, PL81 significantly inhibited the secretion of triacylglycerols(TGs) and phospholipids as part of CM. PL81-treated cells showeddecreased activity of microsomal triglyceride transfer proteinand accumulated more TGs, but not phospholipids, in their cytosol.We propose that Pluronic copolymers act by interfering withthe export of molecules from the cytosol. They inhibit fat absorptionby decreasing TG transport to the endoplasmic reticulum andincrease drug efficacy against cancer cells by competing fortheir excretion.Supplementary key words apolipoprotein B • microsomal triglyceride transfer protein • lipoproteins • phospholipids • enterocytes
Abbreviations: apoB, apolipoprotein B; CM, chylomicron; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein; OA, oleic acid; PL81, Pluronic L81; TC, taurocholate; TG, triacylglycerol
